Iron is an essential element in cellular metabolism. Eukaryotic cells acquire iron through the endocytosis of diferric transferrin mediated by high-affinity transferrin receptors located in their cell membrane. The synthesis, degradation, and cellular dynamics of the transferrin receptor are highly regulated phenomena. In particular, the rate of receptor biosynthesis is altered depending on the state of differentiation and growth of cells. In a proliferating population of cells, the biosynthesis of the transferrin receptor is highly regulated by iron availability. The provision of iron to cells via hemin, inorganic iron salts, or diferric transferrin leads to decreases in the biosynthesis of the receptor. In contrast, intracellular iron chelation results in marked increases in receptor biosynthesis. Modulation of biosynthesis in both directions is a manifestation of corresponding changes in the level of mRNA encoding the receptor. Using the techniques of molecular biology and gene transfer, we are seeking to understand expression a regulation of the transferrin receptor. The promoter region of the receptor has been molecularly cloned and characterized. An enhancer-like element was identified approximately 75 bp upstream of the mRNA start site. A relatively low degree of regulation is conferred by the sequences upstream of the structural gene for the receptor. Rather, the sequences corresponding to the 3' untranslated portion of the mRNA have been implicated as the major locus of iron regulation.